Refining method of bendamustine hydrochloride

A technology of bendamustine hydrochloride and a refining method, which is applied in the field of refining bendamustine hydrochloride, can solve the problems of cumbersome operation, difficult removal of impurities, and influence on the quality of finished products, and achieve simple process, low adverse reactions, Ease of process effect

Inactive Publication Date: 2011-01-19
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Patent WO2009120386 discloses that a refining solvent is ethanol/water (V/V=97/3), but in experiments we found that when refining with alcohol solution, a new impurity (esterification product) will be produced because of heating, because benzene Damustine has a carboxyl group and an alcohol undergoes an esterification reaction at high temperature. If the control is not good, the esterification product will inevitably affect the quality of the finished product, and this impurity will be difficult to remove
The final refining method of Chinese patent CN101691359 is to mix and heat the crude product with tetrahydrofuran (70°C), and then slowly add water until the solid dissolves; THF has a low boiling point (66°C), and when heated to reflux according to this patent method, when adding water dropwise, It is prone to bumping,...

Method used

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  • Refining method of bendamustine hydrochloride
  • Refining method of bendamustine hydrochloride
  • Refining method of bendamustine hydrochloride

Examples

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Effect test

Embodiment 1

[0026] Example 1 Preparation of crude bendamustine hydrochloride

[0027] The crude bendamustine hydrochloride can be prepared by referring to the literature Journal fur praktischeChemie.4.Reihe.Band 20.1963 (178-186), or by referring to the following method:

[0028] (1) Preparation of N-methyl-(2,4-dinitro)aniline (Intermediate 1)

[0029] Add 438g of 2,4-dinitrochlorobenzene, 141g of methylamine hydrochloride, 573g of sodium acetate trihydrate and 1050ml of N,N-dimethylformamide into a 3L three-necked flask, heat to reflux, stir and react for 3h, TLC Stop the reaction after detecting no raw material. The reaction solution was quickly poured into 3000ml of ice water after being slightly cooled, and allowed to stand for crystallization. After filtering, the filter cake is washed with an appropriate amount of water to remove DMF, and the filter cake is dried at 80°C by blowing. A yellow solid 397.3g (Intermediate 1) was obtained, yield: 93.3%, mp: 178.6-179°C.

[0030] (2) Preparat...

Embodiment 2

[0053] Put 5g of bendamustine hydrochloride crude product prepared according to Example 1 (purity 93.2%, maximum single impurities 4.16%) into the reaction flask, add 20g 1mol / L hydrochloric acid solution, heat to 80°C, stir to dissolve, while hot After filtering, the filtrate was cooled to 10°C to crystallize for 12h, filtered, and dried at 45°C for 6h to obtain 4.6g of white solid with a yield of 92%. The purity is 99.84%, the maximum single impurity is 0.05%, and the HPLC purity detection conditions are the same as in Example 1.

Embodiment 3

[0055] Place 9g of crude bendamustine hydrochloride (purity 94.7%, maximum single impurities 4.49%) prepared according to Example 1 in a reaction flask, add 60g of 0.09mol / L hydrochloric acid solution, heat to 50°C, stir to dissolve, add 0.5g of activated carbon was decolorized for 5 minutes, filtered while hot, the filtrate was cooled to 0°C for 5h to crystallize, filtered, and dried at 30°C for 10h to obtain 8.5g of white solid, with a yield of 94.4%. The purity is 99.87%, the maximum single impurity is 0.08%, and the HPLC purity detection conditions are the same as those in Example 1.

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Abstract

The invention provides a refining method of bendamustine hydrochloride, which comprises the following steps: completely dissolving 1 part by weight of bendamustine hydrochloride crude product in 3-10 parts by weight of hydrochloric acid solution with the concentration of 0.01-2mol/L, wherein the temperature is 30-100 DEG C during the dissolution process; and filtering when being hot, cooling, crystallizing, filtering, and drying for obtaining a bendamustine hydrochloride white crystal. The method can effectively remove impurities in the bendamustine hydrochloride crude product, lead the purity of the product to be more than 99.5%, lead single impurity to be not more than 0.1%, and lead the refining yield to be not lower than 90%; in addition, the refining method has simple process, low cost and easy industrial production of the process; and a preparation produced by taking the raw material has few impurities, good efficacy and few adverse reactions, and can bring the greatest benefit to patients with tumors.

Description

Technical field [0001] The invention relates to a method for refining bendamustine hydrochloride, which belongs to the technical field of medicine production. Background technique [0002] The chemical name of bendamustine hydrochloride is [1-methyl-2-(4′-butyric acid)-5-N,N′-bis-(2′-chloroethyl)]-1H-benzimidazole Hydrochloride, the structural formula is: [0003] [0004] Bendamustine hydrochloride was first developed by Ozegowski and his colleagues at the Microbiological Testing Association in Jena, Germany in the early 1860s. The purpose of synthesis is to make an alkylated nitrogen mustard (a non-functional alkylating agent) link a purine and an amino acid. The main advantage of the newly synthesized compound compared with chlorambucil is its water solubility. Anger et al. disclosed the initial clinical results of the successful application of bendamustine to patients with plasmacytoma. Bendamustine was produced by Jena Pharmaceuticals under the trade name Cytostasan from 1...

Claims

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Application Information

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IPC IPC(8): C07D235/16
Inventor 宗在伟陈磊杜有国杨建楠
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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